Despite the undeniable benefit of levodopa, symptomatic treatment for Parkinson's disease (PD) remains suboptimal. As the disease progresses, therapeutic benefit can wane, and significant side effects such as dyskinesias can impose additional limitations. Further, experimental therapeutic approaches such as grafting of replacement dopamine (DA) neurons into patients with PD have produced variable, and overall, disappointing results. Understanding factors that contribute to suboptimal therapeutics in this disease is critical to improving quality of life. While much attention has been focused on approaches to delay degeneration of nigrostriatal neurons, stabilize striatal DA by improved pharmacology, and replace cells lost to the disease, little attention has been given to how the pathological state of the striatum itself might impact DA replacement strategies. It is well documented in postmortem PD brains that there are distinct morphological alterations to striatal medium spiny neurons (MSNs) including significant atrophy of dendritic spines with advanced disease (McNeill et al, 1988;Zaja-Milatovic et al, 2005;Stephens et al, 2005). Such changes would be predicted to negatively impact therapeutic strategies;however, the role of dendritic pathology in PD therapeutics has not been investigated. A recent report (Day et al, 2006) has shown that, as seen in PD patients, severe DA depletion in rats or mice results in a dramatic reduction in spine density on MSNs. Further, these authors have determined that loss of spine density on striatal MSNs is related to dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Identification of this mechanism allows testing of the hypotheses put forth in this application: 1) degenerative changes in spine density of MSNs has a detrimental impact on the efficacy DA replacement therapies, including levodopa and DA grafts;and 2) altered spine morphology plays a role in the development of levodopa- induced and/or graft-induced dyskinetic behaviors. The proposed studies will employ the well-established rat model of parkinsonism &dyskinesia. Using light and electron microscopic analyses &multiple behavioral profiles, we will compare therapeutic benefit and/or development of abnormal behaviors between DA-depleted rats with normal spine morphology and those with significant spine pathology.
Current therapeutics for Parkinson's disease is suboptimal. The proposed studies will explore issues not previously investigated that could have significant clinical significance for development of novel therapeutics for Parkinson's disease.
|Mercado, Natosha M; Collier, Timothy J; Freeman, Thomas et al. (2016) Repairing the Aged Parkinsonian Striatum: Lessons from the Lab and Clinic. J Clin Cell Immunol 7:|
|Collier, Timothy J; O'Malley, Jennifer; Rademacher, David J et al. (2015) Interrogating the aged striatum: robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration. Neurobiol Dis 77:191-203|
|Levine, Nathan D; Rademacher, David J; Collier, Timothy J et al. (2013) Advances in thin tissue Golgi-Cox impregnation: fast, reliable methods for multi-assay analyses in rodent and non-human primate brain. J Neurosci Methods 213:214-27|
|Steece-Collier, Kathy; Rademacher, David J; Soderstrom, Katherine (2012) Anatomy of Graft-induced Dyskinesias: Circuit Remodeling in the Parkinsonian Striatum. Basal Ganglia 2:15-30|
|Soderstrom, Katherine E; O'Malley, Jennifer A; Levine, Nathan D et al. (2010) Impact of dendritic spine preservation in medium spiny neurons on dopamine graft efficacy and the expression of dyskinesias in parkinsonian rats. Eur J Neurosci 31:478-90|
|Steece-Collier, Kathy; Soderstrom, Katherine E; Collier, Timothy J et al. (2009) Effect of levodopa priming on dopamine neuron transplant efficacy and induction of abnormal involuntary movements in parkinsonian rats. J Comp Neurol 515:15-30|
|Soderstrom, K E; Meredith, G; Freeman, T B et al. (2008) The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors. Neurobiol Dis 32:229-42|
|Maries, Eleonora; Kordower, Jeffrey H; Chu, Yaping et al. (2006) Focal not widespread grafts induce novel dyskinetic behavior in parkinsonian rats. Neurobiol Dis 21:165-80|